Papel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta ? radioterapia em gliomas
Ano de defesa: | 2016 |
---|---|
Autor(a) principal: | |
Orientador(a): | |
Banca de defesa: | |
Tipo de documento: | Tese |
Tipo de acesso: | Acesso aberto |
Idioma: | por |
Instituição de defesa: |
Pontif?cia Universidade Cat?lica do Rio Grande do Sul
|
Programa de Pós-Graduação: |
Programa de P?s-Gradua??o em Biologia Celular e Molecular
|
Departamento: |
Faculdade de Bioci?ncias
|
País: |
Brasil
|
Palavras-chave em Português: | |
Área do conhecimento CNPq: | |
Link de acesso: | http://tede2.pucrs.br/tede2/handle/tede/6652 |
Resumo: | Gliomas represent the most common class of malignant tumors of the central nervous system being the most aggressive, and lethal brain tumors in primary brain tumors. Among the treatments, radiation is one of the most used therapies, but the intrinsic radioresistance of these tumors remains a critical problem in the management of these patients. Currently it is known that the effect of radiation extends beyond the directly cytotoxicity caused in tumor cells. Radiation therapy appears to induce an immunogenic cell death that among the features is ATP release. The ATP can cause cytotoxicity via P2X7 receptor and also acts as a sign of damage activating the immune system. The ATP can be hydrolyzed by enzymes of the purinergic system, among them the ectonucleotidase CD39, to adenosine, which has an opposite effect to ATP, causing immunosuppression. The radiation-induced ATP release and the ability of this nucleotide in modulate immune responses raised the hypothesis about the purinergic signaling participation in the tumor and immune cells response to radiation. Therefore, this study investigated: i) the role of ectonucleotidase CD39/NTPDase1 in the radiation-induced immune response in gliomas, ii) the importance of ATP-P2X7 receptor in the gliomas response to radiotherapy. Using knockout mice for CD39/NTPDase1, we observed that the deletion of this enzyme combined with radiotherapy significantly reduced the immunosuppressive cells Tregs in the tumor and spleen, attenuated the infiltration of myeloid derived suppressor cells caused by radiation and increased CCR7 expression in splenic dendritic cells and macrophages, indicating the presence of freshly mobilized antigen presenting cells available to differentiate in immune-effector cells that sustain a more prolonged antigen-specific T-cell?mediated immune response. Thereby, showing that blocking the activity of CD39/NTPDase1 can control immunosuppressive mechanisms generated by the tumor and promises to improve the radiotherapy response. Furthermore, in this study we observed that radiation actives the P2X7 receptor and by silencing this receptor on the GL261 glioma cell line, we have shown that radiotherapy is less efficient in vivo when compared with mice injected with GL261 WT cells, which constitutively express the P2X7 receptor. We also showed that patients with glioma that overexpress the P2X7 receptor, showed a better response to radiotherapy, revealing the importance of the expression of this receptor on glioma cells as a useful marker to analyze the tumor sensitivity to radiation and a successful radiotherapy response. In summary, our data shed light on the purinergic signaling for modulating the radiotherapy response in gliomas. |
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Morrone, Fernanda Bueno462.631.280-20http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4707416P4020.647.450-41http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4203373P6Gehring, Marina Petersen2016-05-10T11:19:25Z2016-01-11http://tede2.pucrs.br/tede2/handle/tede/6652Gliomas represent the most common class of malignant tumors of the central nervous system being the most aggressive, and lethal brain tumors in primary brain tumors. Among the treatments, radiation is one of the most used therapies, but the intrinsic radioresistance of these tumors remains a critical problem in the management of these patients. Currently it is known that the effect of radiation extends beyond the directly cytotoxicity caused in tumor cells. Radiation therapy appears to induce an immunogenic cell death that among the features is ATP release. The ATP can cause cytotoxicity via P2X7 receptor and also acts as a sign of damage activating the immune system. The ATP can be hydrolyzed by enzymes of the purinergic system, among them the ectonucleotidase CD39, to adenosine, which has an opposite effect to ATP, causing immunosuppression. The radiation-induced ATP release and the ability of this nucleotide in modulate immune responses raised the hypothesis about the purinergic signaling participation in the tumor and immune cells response to radiation. Therefore, this study investigated: i) the role of ectonucleotidase CD39/NTPDase1 in the radiation-induced immune response in gliomas, ii) the importance of ATP-P2X7 receptor in the gliomas response to radiotherapy. Using knockout mice for CD39/NTPDase1, we observed that the deletion of this enzyme combined with radiotherapy significantly reduced the immunosuppressive cells Tregs in the tumor and spleen, attenuated the infiltration of myeloid derived suppressor cells caused by radiation and increased CCR7 expression in splenic dendritic cells and macrophages, indicating the presence of freshly mobilized antigen presenting cells available to differentiate in immune-effector cells that sustain a more prolonged antigen-specific T-cell?mediated immune response. Thereby, showing that blocking the activity of CD39/NTPDase1 can control immunosuppressive mechanisms generated by the tumor and promises to improve the radiotherapy response. Furthermore, in this study we observed that radiation actives the P2X7 receptor and by silencing this receptor on the GL261 glioma cell line, we have shown that radiotherapy is less efficient in vivo when compared with mice injected with GL261 WT cells, which constitutively express the P2X7 receptor. We also showed that patients with glioma that overexpress the P2X7 receptor, showed a better response to radiotherapy, revealing the importance of the expression of this receptor on glioma cells as a useful marker to analyze the tumor sensitivity to radiation and a successful radiotherapy response. In summary, our data shed light on the purinergic signaling for modulating the radiotherapy response in gliomas.Os gliomas representam a classe mais comum de tumores malignos do sistema nervoso central, sendo o tumor cerebral mais agressivo e letal entre os tumores cerebrais prim?rios. Dentre os tratamentos, a radia??o ? uma das terapias mais utilizadas, por?m a radiorresist?ncia intr?nseca destes tumores continua a ser um problema cr?tico na gest?o de destes pacientes. Atualmente, sabe-se que o efeito da radia??o se estende al?m da citotoxicidade direta causada nas c?lulas tumorais. A radioterapia parece induzir uma morte celular imunog?nica, que entre as caracter?sticas est? a libera??o de ATP. O ATP pode causar citotoxicidade atrav?s do receptor P2X7 e tamb?m atua como um sinal de dano celular ativando o sistema imune. O ATP pode ser hidrolisado por enzimas do sistema purin?rgico, dentre elas a ectonucleotidase CD39/NTPDase1, ? adenosina, que tem um efeito aposto ao ATP, causando imunossupress?o. A secre??o de ATP induzida pela radioterapia e a capacidade deste nucleot?deo em modular a resposta imune, levantou a hip?tese da participa??o da sinaliza??o purin?rgica na resposta de c?lulas tumorais ? radia??o e na resposta imune induzida pela radioterapia. Portanto, neste estudo visou-se investigar: i) o papel da ectonucleotidase CD39/NTPDase1 na resposta imune induzida pela radioterapia em gliomas, ii) a import?ncia da via ATP-receptor P2X7 na resposta de gliomas ? radioterapia. Atrav?s de camundongos knockout para a enzima CD39/NTPDase1, observamos que a dele??o desta enzima combinada com a radioterapia reduziu significativamente as c?lulas imunossupressoras Tregs no tumor e no ba?o, atenuou a infiltra??o de c?lulas mieloides supressoras causada pela radia??o, e aumentou a express?o de CCR7 em c?lulas dentr?ticas e macr?fagos localizados no ba?o, indicando a presen?a c?lulas apresentadoras de ant?geno rec?mmobilizadas e dispon?veis para se diferenciarem em c?lulas imunes efetoras que sustentam uma resposta imune mais prolongada mediada por c?lulas T ant?geno espec?ficas. Deste modo, mostrou-se que o bloqueio da atividade da CD39/NTPDase1 pode controlar mecanismos imunossupressores gerados pelo tumor e promete melhorar a resposta ? radioterapia. Al?m disso, neste estudo observou-se que a radioterapia ativa o receptor P2X7 e atrav?s do silenciamento deste receptor na linhagem de glioma GL261, demonstramos que a radioterapia foi pouco eficiente in vivo, quando comparado com camundongos injetados com a GL261 WT, que expressa constitutivamente o receptor P2X7. Tamb?m demonstramos que pacientes com glioma que expressaram mais o receptor P2X7, apresentaram uma melhor resposta a radioterapia, revelando a import?ncia da express?o deste receptor em c?lulas de glioma como um marcador ?til para analisar a sensibilidade tumoral ? radioterapia e para uma resposta bem-sucedida ? radioterapia. Em suma, nossos dados lan?am luz sobre a sinaliza??o purin?rgica para a modula??o da resposta ? radioterapia em gliomas.Submitted by Setor de Tratamento da Informa??o - BC/PUCRS (tede2@pucrs.br) on 2016-05-10T11:19:25Z No. of bitstreams: 1 TES_MARINA_PETERSEN_GEHRING_COMPLETO.pdf: 5818535 bytes, checksum: 5b089589ca820b17117fd0c8e9d1cc90 (MD5)Made available in DSpace on 2016-05-10T11:19:25Z (GMT). No. of bitstreams: 1 TES_MARINA_PETERSEN_GEHRING_COMPLETO.pdf: 5818535 bytes, checksum: 5b089589ca820b17117fd0c8e9d1cc90 (MD5) Previous issue date: 2016-01-11Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPESapplication/pdfhttp://tede2.pucrs.br:80/tede2/retrieve/164789/TES_MARINA_PETERSEN_GEHRING_COMPLETO.pdf.jpgporPontif?cia Universidade Cat?lica do Rio Grande do SulPrograma de P?s-Gradua??o em Biologia Celular e MolecularPUCRSBrasilFaculdade de Bioci?nciasTRIFOSFATO DE ADENOSINAGLIOMASRADIOTERAPIABIOLOGIA CELULARBIOLOGIA MOLECULARCIENCIAS BIOLOGICAS::BIOLOGIA GERALPapel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta ? radioterapia em gliomasinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesis819824693009663736060060060060036528317262667714-16345593859312446972075167498588264571info:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da PUC_RSinstname:Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS)instacron:PUC_RSTHUMBNAILTES_MARINA_PETERSEN_GEHRING_COMPLETO.pdf.jpgTES_MARINA_PETERSEN_GEHRING_COMPLETO.pdf.jpgimage/jpeg3655http://tede2.pucrs.br/tede2/bitstream/tede/6652/4/TES_MARINA_PETERSEN_GEHRING_COMPLETO.pdf.jpgae9686f1d4c362bf054d32502f1e2517MD54TEXTTES_MARINA_PETERSEN_GEHRING_COMPLETO.pdf.txtTES_MARINA_PETERSEN_GEHRING_COMPLETO.pdf.txttext/plain397815http://tede2.pucrs.br/tede2/bitstream/tede/6652/3/TES_MARINA_PETERSEN_GEHRING_COMPLETO.pdf.txt4c445c973309f7d9ae2e995306b52f9aMD53ORIGINALTES_MARINA_PETERSEN_GEHRING_COMPLETO.pdfTES_MARINA_PETERSEN_GEHRING_COMPLETO.pdfapplication/pdf5818535http://tede2.pucrs.br/tede2/bitstream/tede/6652/2/TES_MARINA_PETERSEN_GEHRING_COMPLETO.pdf5b089589ca820b17117fd0c8e9d1cc90MD52LICENSElicense.txtlicense.txttext/plain; charset=utf-8610http://tede2.pucrs.br/tede2/bitstream/tede/6652/1/license.txt5a9d6006225b368ef605ba16b4f6d1beMD51tede/66522016-05-10 12:01:12.299oai:tede2.pucrs.br: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Biblioteca Digital de Teses e Dissertaçõeshttp://tede2.pucrs.br/tede2/PRIhttps://tede2.pucrs.br/oai/requestbiblioteca.central@pucrs.br||opendoar:2016-05-10T15:01:12Biblioteca Digital de Teses e Dissertações da PUC_RS - Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS)false |
dc.title.por.fl_str_mv |
Papel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta ? radioterapia em gliomas |
title |
Papel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta ? radioterapia em gliomas |
spellingShingle |
Papel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta ? radioterapia em gliomas Gehring, Marina Petersen TRIFOSFATO DE ADENOSINA GLIOMAS RADIOTERAPIA BIOLOGIA CELULAR BIOLOGIA MOLECULAR CIENCIAS BIOLOGICAS::BIOLOGIA GERAL |
title_short |
Papel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta ? radioterapia em gliomas |
title_full |
Papel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta ? radioterapia em gliomas |
title_fullStr |
Papel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta ? radioterapia em gliomas |
title_full_unstemmed |
Papel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta ? radioterapia em gliomas |
title_sort |
Papel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta ? radioterapia em gliomas |
author |
Gehring, Marina Petersen |
author_facet |
Gehring, Marina Petersen |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Morrone, Fernanda Bueno |
dc.contributor.advisor1ID.fl_str_mv |
462.631.280-20 |
dc.contributor.advisor1Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4707416P4 |
dc.contributor.authorID.fl_str_mv |
020.647.450-41 |
dc.contributor.authorLattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4203373P6 |
dc.contributor.author.fl_str_mv |
Gehring, Marina Petersen |
contributor_str_mv |
Morrone, Fernanda Bueno |
dc.subject.por.fl_str_mv |
TRIFOSFATO DE ADENOSINA GLIOMAS RADIOTERAPIA BIOLOGIA CELULAR BIOLOGIA MOLECULAR |
topic |
TRIFOSFATO DE ADENOSINA GLIOMAS RADIOTERAPIA BIOLOGIA CELULAR BIOLOGIA MOLECULAR CIENCIAS BIOLOGICAS::BIOLOGIA GERAL |
dc.subject.cnpq.fl_str_mv |
CIENCIAS BIOLOGICAS::BIOLOGIA GERAL |
description |
Gliomas represent the most common class of malignant tumors of the central nervous system being the most aggressive, and lethal brain tumors in primary brain tumors. Among the treatments, radiation is one of the most used therapies, but the intrinsic radioresistance of these tumors remains a critical problem in the management of these patients. Currently it is known that the effect of radiation extends beyond the directly cytotoxicity caused in tumor cells. Radiation therapy appears to induce an immunogenic cell death that among the features is ATP release. The ATP can cause cytotoxicity via P2X7 receptor and also acts as a sign of damage activating the immune system. The ATP can be hydrolyzed by enzymes of the purinergic system, among them the ectonucleotidase CD39, to adenosine, which has an opposite effect to ATP, causing immunosuppression. The radiation-induced ATP release and the ability of this nucleotide in modulate immune responses raised the hypothesis about the purinergic signaling participation in the tumor and immune cells response to radiation. Therefore, this study investigated: i) the role of ectonucleotidase CD39/NTPDase1 in the radiation-induced immune response in gliomas, ii) the importance of ATP-P2X7 receptor in the gliomas response to radiotherapy. Using knockout mice for CD39/NTPDase1, we observed that the deletion of this enzyme combined with radiotherapy significantly reduced the immunosuppressive cells Tregs in the tumor and spleen, attenuated the infiltration of myeloid derived suppressor cells caused by radiation and increased CCR7 expression in splenic dendritic cells and macrophages, indicating the presence of freshly mobilized antigen presenting cells available to differentiate in immune-effector cells that sustain a more prolonged antigen-specific T-cell?mediated immune response. Thereby, showing that blocking the activity of CD39/NTPDase1 can control immunosuppressive mechanisms generated by the tumor and promises to improve the radiotherapy response. Furthermore, in this study we observed that radiation actives the P2X7 receptor and by silencing this receptor on the GL261 glioma cell line, we have shown that radiotherapy is less efficient in vivo when compared with mice injected with GL261 WT cells, which constitutively express the P2X7 receptor. We also showed that patients with glioma that overexpress the P2X7 receptor, showed a better response to radiotherapy, revealing the importance of the expression of this receptor on glioma cells as a useful marker to analyze the tumor sensitivity to radiation and a successful radiotherapy response. In summary, our data shed light on the purinergic signaling for modulating the radiotherapy response in gliomas. |
publishDate |
2016 |
dc.date.accessioned.fl_str_mv |
2016-05-10T11:19:25Z |
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2016-01-11 |
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Pontif?cia Universidade Cat?lica do Rio Grande do Sul |
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Programa de P?s-Gradua??o em Biologia Celular e Molecular |
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